Activation of farnesoid X receptor enhances the efficacy of normothermic machine perfusion in ameliorating liver ischemia-reperfusion injury.

The shortage of transplant organs remains a severe global issue. Normothermic machine perfusion (NMP) has the potential to increase organ availability, yet its efficacy is hampered by the inflammatory response during machine perfusion. Mouse liver ischemia-reperfusion injury (IRI) models, discarded human liver models, and porcine marginal liver transplantation models were utilized to investigate whether farnesoid X receptor (FXR) activation could mitigate inflammation-induced liver damage. FXR expression levels before and after reperfusion were measured. Gene editing and coimmunoprecipitation techniques were employed to explore the regulatory mechanism of FXR in inflammation inhibition. The expression of FXR correlates with the extent of liver damage after reperfusion. Activation of FXR significantly suppressed the inflammatory response triggered by IRI, diminished the release of proinflammatory cytokines, and improved liver function recovery during NMP, assisting discarded human livers to reach transplant standards. Mechanistically, FXR disrupts the interaction between p65 and p300, thus inhibiting modulating the nuclear factor kappa-B signaling pathway, a key instigator of inflammation. Our research across multiple species confirms that activating FXR can optimize NMP by attenuating IRI-related liver damage, thereby improving the utilization of marginal livers for transplantation.

Optimizing Intermediate Adsorption over PdM (M=Fe, Co, Ni, Cu) Bimetallene for Boosted Nitrate Electroreduction to Ammonia.

Electrochemical reduction of nitrate to ammonia (NO3RR) is a promising and eco-friendly strategy for ammonia production. However, the sluggish kinetics of the eight-electron transfer process and poor mechanistic understanding strongly impedes its application. To unveil the internal laws, herein, a library of Pd-based bimetallene with various transition metal dopants (PdM (M=Fe, Co, Ni, Cu)) are screened to learn their structure-activity relationship towards NO3RR. The ultra-thin structure of metallene greatly facilitates the exposure of active sites, and the transition metals dopants break the electronic balance and upshift its d-band center, thus optimizing intermediates adsorption. The anisotropic electronic characteristics of these transition metals make the NO3RR activity in the order of PdCu>PdCo≈PdFe>PdNi>Pd, and a record-high NH3 yield rate of 295 mg h-1 mgcat -1 along with Faradaic efficiency of 90.9 % is achieved in neutral electrolyte on PdCu bimetallene. Detailed studies further reveal that the moderate N-species (*NO3 and *NO2) adsorption ability, enhanced *NO activation, and reduced HER activity facilitate the NH3 production. We believe our results will give a systematic guidance to the future design of NO3RR catalysts.

Atomic layer deposition assisted fabrication of large-scale metal nanogaps for surface enhanced Raman scattering.

Metal nanogaps can confine electromagnetic field into extremely small volumes, exhibiting strong surface plasmon resonance effect. Therefore, metal nanogaps show great prospects in enhancing light-matter interaction. However, it is still challenging to fabricate large-scale (centimeter scale) nanogaps with precise control of gap size at nanoscale, limiting the practical applications of metal nanogaps. In this work, we proposed a facile and economic strategy to fabricate large-scale sub-10 nm Ag nanogaps by the combination of atomic layer deposition (ALD) and mechanical rolling. The plasmonic nanogaps can be formed in the compacted Ag film by the sacrificial Al2O3deposited via ALD. The size of nanogaps are determined by the twice thickness of Al2O3with nanometric control. Raman results show that SERS activity depends closely on the nanogap size, and 4 nm Ag nanogaps exhibit the best SERS activity. By combining with other porous metal substrates, various sub-10 nm metal nanogaps can be fabricated over large scale. Therefore, this strategy will have significant implications for the preparation of nanogaps and enhanced spectroscopy.

Terahertz nonreciprocal and functionality-switchable devices based on dielectric multilayers integrated with graphene and VO2.

Recently, terahertz (THz) nonreciprocal and functionality-switchable devices have drawn much attention. Here we report a magnetic-free THz unidirectional perfect absorber as well as a functionality-switchable device between the band-pass filter and perfect absorber based on dielectric-graphene multilayers containing a VO2 defect layer. We provide a theoretical explanation for the nonreciprocal transmission properties. The working frequencies of these devices can be tailored by using graphene layers of different chemical potentials.

Multifunctional and wavelength division multiplexing all-optical logic gates based on four-port metal-insulator-metal waveguides coupled with a ring resonator.

In the past few years, designing multifunctional all-optical logic devices has attracted more and more attention in integrated optical computing. We report a metal-insulator-metal based four-port all-optical logic gate device containing two parallel straight waveguides and a ring resonator. We employ the scattering matrix method to analyze the coupling mechanisms of the hybrid waveguide and adopt the finite-difference time-domain method to design four fundamental logic functions of AND, OR, XOR, and NOT based on the all-optical coherent control of the four-port system under three symmetrically incident conditions. We demonstrate that these logic functions can be freely modulated by changing the phase difference of the input light at two resonant wavelengths or in a broad band. The logic gate device proposed shows a simple structure with multiple functions, multiple channels, and convenience in fabrication, and can be applied in parallel optical computing based on wavelength division multiplexing technology.

Tunable and multifunctional terahertz devices based on one-dimensional anisotropic photonic crystals containing graphene and phase-change material.

In the past few years, designing tunable and multifunctional terahertz devices has become a hot research area in terahertz science and technology. In this work, we report a study on one-dimensional anisotropic photonic crystals (1D APCs) containing graphene and phase-change material VO2. We numerically demonstrate the band-pass filtering, perfect absorption, comb-shaped extraordinary optical transmission and Fano-like resonance phenomenon in pure 1D APCs and 1D APCs with a VO2 defect layer under different conditions of a tangential wave vector. The performance of these phenomena in the terahertz region can be modulated by changing the chemical potential of graphene. The band-pass filter and perfect absorber functions of 1D APCs with a VO2 defect layer can be freely switched by changing the phase of VO2. We employ the equivalent-permittivity model and dispersion-relation equation to give reasonable explanations on these behaviors.

Association of Perfusion Characteristics and Posttransplant Liver Function in Ischemia-Free Liver Transplantation.

It has been shown that normothermic machine perfusion (NMP), a novel preservation method, is able to assess and resuscitate liver grafts with risk factors. However, there is no consistent criteria for the assessment of liver grafts with NMP. Ischemia-free liver transplantation (IFLT) includes innovative surgical techniques and NMP, which can protect liver grafts from ischemia throughout organ procurement, preservation, and implantation. In our center, 28 human livers from donation after brain death donors were subjected to IFLT between July 2017 and October 2018. The correlation between posttransplant liver function tests with the perfusion parameters, blood gas analysis of perfusate, and bile biochemistry were analyzed. During the preservation phase, the vascular flow was stable, and the lactate level decreased rapidly. The transaminase release in the perfusate was low but stable, whereas the glucose level remained high. The perfusate lactate and aspartate aminotransferase (AST) levels at 1 hour of perfusion were correlated with the posttransplant peak AST level. There were negative correlations between the portal vein and hepatic artery flows at the end of perfusion and the peak transaminase levels within 7 days after transplantation. In conclusion, during IFLT, NMP is able to bridge the liver grafts from donors to recipients and can allow the assessment of liver function by perfusion characteristics.

Multifunctional and multichannel all-optical logic gates based on the in-plane coherent control of localized surface plasmons.

In this Letter, we report a scheme to design multifunctional and multichannel all-optical logic gates based on the in-plane coherent control of localized surface plasmons in an Au nanorod (NR) array on the Si substrate. By using theoretical analysis and structural optimization, we numerically demonstrate a four-channel all-optical logic gate device that can switch three basic logic operations on each NR only by controlling the phase differences of incident beams. This device is ultra-compact in size and shows high extensibility for parallel logic operations, which may be applied in future high-speed on-chip integrated optical computing.

Bioinformatics analysis on multiple Gene Expression Omnibus datasets of the hepatitis B virus infection and its response to the interferon-alpha therapy.

BACKGROUND: Hepatitis B virus (HBV) infection is a global health problem and interferon-alpha (IFN-α) is one of the effective therapies. However, little is known about the genetic background of the HBV infection or the genetic determinants of the IFN-α treatment response. Thus, we aim to explore the possible molecular mechanisms of HBV infection and its response to the IFN-α therapy with a comprehensive bioinformatics analysis. METHODS: The Gene Expression Omnibus datasets (GSE83148, GSE84044 and GSE66698) were collected and the differentially expressed genes (DEGs), key biological processes and intersecting pathways were analyzed. The expression of the co-expressed DEGs in the clinical samples was verified by quantitative real time polymerase chain reaction (qRT-PCR). RESULTS: Analysis of all the 3 datasets revealed that there were eight up-regulated and one down-regulated co-expressed DEGs following the HBV infection and after IFN-α treatment. In clinical samples, the mRNA level of HKDC1, EPCAM, GSN, ZWINT and PLD3 were significantly increased, while, the mRNA level of PLEKHA2 was significantly decreased in HBV infected liver tissues compared to normal liver tissues. PI3K-Akt signaling pathway, focal adhesion, HTLV-I infection, cytokine-cytokine receptor interaction, metabolic pathways, NF-κB signaling pathway were important pathways associated with the HBV infection and the response of IFN-α treatment. CONCLUSIONS: The co-expressed genes, common biological processes and intersecting pathways identified in the study might play an important role in HBV infection and response of IFN-α treatment. The dysregulated genes may act as novel biomarkers and therapeutic targets for HBV.

Static pure strain sensing using dual-comb spectroscopy with FBG sensors.

We propose a method to precisely characterize the optical response of a fiber Bragg grating (FBG) sensor for static strain sensing by using dual-comb spectroscopy (DCS). By digitally post-correcting the mutual noise between the two combs, a robust and pure strain sensing system is achieved by compensating for the temperature-induced frequency shift of the FBG sensor. The comb-resolved radio-frequency (RF) spectra generated by DCS are obtained. Meanwhile, the stability of the central Bragg frequency of the FBG-reflected spectrum in the RF domain is 0.315 kHz, which is better than the difference of repetition rate (1 kHz). A reference FBG is used for detecting and compensating for the temperature-induced central frequency drift. Finally, a spectral sensitivity of 0.85 pm/µÉ› with 0.8 µÉ› static strain resolution is achieved.

Two-color phase-stable dual-comb ranging without precise environmental sensing.

High-precision long geometrical distance measurement performs a vital role in large-scale manufacturing and future light detection and ranging (LIDAR) for tight formation. Its high precision, fast measurement rate, and large ambiguity range have traditionally made dual-comb ranging (DCR) a powerful tool for absolute distance measurement. However, DCR experiences the same issues caused by the refractive index of air as other laser-based ranging systems. The conventional method used to compensate refractive index of air is through using empirical equations by monitoring environment parameters. This real-time compensation method relies on precise sensors and cannot be easily applied to long-distance measurement. Thus, a two-color compensation method is proposed that requires only two co-propagating lights at different wavelengths, without specific identification of the refractive index of air. In this paper, the two-color method is combined with a low-noise DCR realized by a digital correction method. Mode resolved and phase-stable comb spectra are available for ranging at both two wavelengths with ~200 THz difference. The experimental result demonstrates 46 nm precision and 2.7 m ambiguity range by two-color DCR (TC-DCR) with 0.1 s coherent averaging at 1 kHz repetition rate difference. This method achieves a precision of the order of ~10-8 and an accuracy of the order of ~10-7, which is comparable to the single-color DCR results by empirical equations with environmental sensing. The proposed two-color DCR demonstrates great potential for long-distance measurement in open air.

Simplified phase-stable dual-comb interferometer for short dynamic range distance measurement.

A simplified phase-stable dual-comb interferometer for absolute distance measurement within a short dynamic range is proposed in this paper. The experimental results demonstrate that stable phase-difference information and lower timing jitter can be obtained within a time delay of 2000 ns between the reference interference signal and measurement interference signal. Using the proposed technique, the time-of-flight (TOF) result can link directly to the carrier-wave interferometric (CWI) result in an average time of 20 ms and can reach 2 nm precision in 0.5 s averaging time. Millimeter-scale measurement dynamic range and nanometer-level precision can thus be achieved without additional noise suppression. This method can also be applied at different stand-off distances.

lncRNA XIST regulates proliferation and migration of hepatocellular carcinoma cells by acting as miR-497-5p molecular sponge and targeting PDCD4.

BACKGROUND: MicroRNAs (miRNAs) play a pivotal role in hepatocellular carcinoma (HCC) progression and have been confirmed to participate in the carcinogenesis and development of HCC. However, the relationship between miR-497-5p and HCC remains unclear. METHODS: Kaplan-Meier curve analysis and the log-rank test were used to investigate the efficacy of miR-497-5p on overall survival (OS) and disease-free survival (DFS) in patients with HCC. According to in vitro experiments, programmed cell death 4 (PDCD4) was a target of miR-497-5p by the dual-luciferase activity assay. The efficacy of PDCD4 on cell proliferation and metastasis in HCC was examined by transwell assays, CCK-8 assays and reverse transcription quantitative PCR (RT-qPCR). Additionally, we conducted a luciferase activity reporter assay to confirm the interaction between lncRNA XIST and miR-49-5p. Then, to evaluate the relationship between lncRNA XIST and miR-497-5p, several mechanistic experiments, including qRT-PCR, Western blotting, transwell assays and tumor xenograft assays, were performed. RESULTS: miR-497-5p was upregulated in HCC tissues, and high expression of miR-497-5p resulted in increases in tumor size and tumor number and a higher tumor-node-metastasis (TNM) stage and Edmondson grade in patients with HCC. Silencing miR-497-5p inhibited the proliferation and migration of HCC cells. PDCD4, which was downregulated in HCC tissues, was shown to be a target of miR-497-5p and was negatively correlated with the expression of miR-497-5p. lncRNA XIST was found to act as a miR-497-5p sponge and to regulate the level of PDCD4, which is targeted by miR-497-5p. lncRNA XIST was observed to be downregulated in the HCC tissues and positively correlated with the expression of PDCD4. CONCLUSIONS: Our findings reveal that the XIST/miR-497-5p/PDCD4 axis participates in HCC development and that XIST could be used as a biomarker of HCC.

The first case of ischemia-free organ transplantation in humans: A proof of concept.

Ischemia and reperfusion injury (IRI) is an inevitable event in conventional organ transplant procedure and is associated with significant mortality and morbidity post-transplantation. We hypothesize that IRI is avoidable if the blood supply for the organ is not stopped, thus resulting in optimal transplant outcomes. Here we described the first case of a novel procedure called ischemia-free organ transplantation (IFOT) for patients with end-stage liver disease. The liver graft with severe macrovesicular steatosis was donated from a 25-year-old man. The recipient was a 51-year-old man with decompensated liver cirrhosis and hepatocellular carcinoma. The graft was procured, preserved, and implanted under continuous normothermic machine perfusion. The recipient did not suffer post-reperfusion syndrome or vasoplegia after revascularization of the allograft. The liver function test and histological study revealed minimal hepatocyte, biliary epithelium and vascular endothelium injury during preservation and post-transplantation. The inflammatory cytokine levels were much lower in IFOT than those in conventional procedure. Key pathways involved in IRI were not activated after allograft revascularization. No rejection, or vascular or biliary complications occurred. The patient was discharged on day 18 post-transplantation. This marks the first case of IFOT in humans, offering opportunities to optimize transplant outcomes and maximize donor organ utilization.

Combined liver-kidney perfusion enhances protective effects of normothermic perfusion on liver grafts from donation after cardiac death.

It has been shown that combined liver-kidney normothermic machine perfusion (NMP) is able to better maintain the circuit's biochemical milieu. Nevertheless, whether the combined perfusion is superior to liver perfusion alone in protecting livers from donation after circulatory death (DCD) is unclear. We aimed to test the hypothesis and explored the mechanisms. Livers from 15 DCD pig donors were subjected to either static cold storage (group A), liver-alone NMP (group B), or combined liver-kidney NMP (group C). Livers were preserved for 6 hours and reperfused ex vivo for 2 hours to simulate transplantation or were transplanted in situ. During perfusion, group C showed an improved acid-base and biochemical environment in the circuit over group B. After reperfusion, the architecture of the liver grafts was best preserved in group C, followed by group B, then group A, as shown by the histology and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling staining of both hepatocytes and biliary epithelium. Ki-67 staining showed substantial hepatocyte proliferation and biliary epithelial regeneration after perfusion in group B and group C. Group C produced more bile in the reperfusion phase than those in group A and group B, with more physiological bile composition and less severe biliary epithelium injury. Von Willebrand factor-positive endothelial cells and E-selectin expression decreased in both group B and group C. Combined liver-kidney NMP not only produced more adenosine triphosphate, protected the nitric oxide signaling pathway, but also diminished oxidative stress (high mobility group box-1 protein and 8-hydroxy-2-deoxy guanosine levels) and inflammatory cytokine (IL6 and IL8) release when compared with liver-alone NMP and CS. In addition, the 7-day survival rate of liver transplant recipients was higher in group C than that in groups A and B. In conclusion, combined liver-kidney NMP can better protect DCD livers from warm ischemia and reperfusion injury probably by maintaining the stability of the internal environment and by abolishing oxidative stress injury. Liver Transplantation 24 67-79 2018 AASLD.

Synthetic-wavelength-based dual-comb interferometry for fast and precise absolute distance measurement.

We present an absolute distance measurement system using a phase-stable dual-comb system with 56.09 MHz repetition rate and 2 kHz repetition rate difference. A relative phase stability of 0.1 rad in 0.5 ms between two combs is achieved using a mutual locking scheme. The dual-comb ranging system combines the time-of-flight (TOF) method, synthetic-wavelength interferometry (SWI), and carrier wave interferometry (CWI). Each method provides a particular ambiguity range and resolution, and they can be applied simultaneously and linked to enhance the precision and measurement rate of the ranging system. The experimental results demonstrate that a precision of 1.2 µm is obtained without time averaging, and the precision can be improved to 3 nm with only 10 ms averaging time using the SWI method described in this study. The precision reaches a sub-nanometer when the averaging time exceeds 0.1 s. A system with high accuracy and short averaging time would enhance fast measurement performance in various industrial applications. The ambiguity range is about 2.67 m in our system, we test the performance of the system with 1.5 mm range at 1.5 m distance.

Digital correction method for realizing a phase-stable dual-comb interferometer.

A phase-stable dual-comb interferometer measures materials' broadband optical response functions, including amplitude, frequency, and phase, making it a powerful tool for optical metrology. Normally, the phase-stable dual-comb interferometer is realized via tight phase-locking methods. This paper presents a post-correction algorithm that can compensate for carrier wave phase noise and interferogram timing jitter. The compensating signal is a beat between two combs using a free-running continuous wave laser as an optical intermediary. In our experiment, sub-hertz relative linewidth, ~1 ns relative timing jitter, and 0.2 rad precision in the carrier phase is demonstrated.

Donor liver apoptosis is associated with early allograft dysfunction and decreased short-term graft survival after liver transplantation.

BACKGROUND: The clinical significance of apoptosis in assessing the quality of donor liver grafts remains unknown. AIMS: This study aimed to determine whether apoptosis in a donor liver is predictive of early allograft dysfunction (EAD) and graft survival after liver transplantation (LT). METHODS: Donor liver specimens were analyzed for apoptosis using TUNEL assays. The prognostic factors for EAD were identified through logistic regression analyses, and a nomogram was developed. RESULTS: The apoptosis index of donor livers in EAD patients was significantly higher than that of donors livers in non-EAD patients (median 5.3; interquartile range [IQR] 3.4 vs 3.5; 3.6, P < 0.001). Multivariate analyses identified the apoptosis index of the donor liver (HR = 6.927, P < 0.001) and five other characteristics as independent predictors of EAD. A nomogram built on these predictive variables showed good calibration and discriminatory abilities, with a c-index value of 0.847. The 30-day graft survival rates in the high apoptosis index (apoptosis index >4.4%) group were significantly lower than those in the low apoptosis index (apoptosis index ≤4.4%) group (84.4% vs 97.6%, P = 0.004). CONCLUSIONS: Donor liver apoptosis plays a significant role in predicting EAD after LT. Furthermore, a high apoptosis index in the donor liver was associated with inferior graft survival in the short-term.

Receiving Hypertensive Donor Grafts Is Associated with Inferior Prognosis in Simultaneous Liver-Kidney Transplantation Recipients.

BACKGROUND The impact of hypertensive (HTN) donor grafts on the prognosis of simultaneous liver-kidney transplantation (SLKT) patient is not known, and an applicable risk scoring system for SLKT patient survival is lacking. This study aimed to evaluate the impact of donor HTN on patient survival of SLKT recipients and to identify independent risk factors. MATERIAL AND METHODS Data from 3844 adult SLKT recipients receiving deceased donor grafts from March 2002 to December 2014 in the Scientific Registry of Transplant Recipients (SRTR) database were retrospectively analyzed. Kaplan-Meier analysis was used to compare patient and graft survival. Multivariate Cox proportional hazard models were built to identify independent risk factors associated with patient and graft survival. RESULTS SLKT patients receiving HTN donor grafts had significantly shorter 5-year patient survival and kidney graft survival rates than did those receiving non-HTN donor grafts (50.1% vs. 63.2%, p<0.0001 and 45.4% vs. 67.8%, p<0.0001, respectively). Multivariate analysis identified HTN donor, donor age, donation after cardiac death, cold ischemia time, recipient age, recipient condition at transplant, recipient hepatitis C infection, need for life support, and recipient pre-transplant albumin level as independent risk factors associated with inferior patient survival in SLKT recipients. A risk scoring model that predicted excellent stratification of prognostic subgroups was established (AUC, 0.762; 95% CI, 0.739-0.785). CONCLUSIONS An SLKT patient receiving a graft from an HTN donor has an inferior prognosis. A risk scoring system applicable to patient survival in SLKT recipients was developed.

Outcomes of Organ Transplantation from Donors with a Cancer History.

BACKGROUND The inherent challenges of selecting an acceptable donor for the increasing number and acuity of recipients has forced programs to take increased risks, including accepting donors with a cancer history (DWCH). Outcomes of organ transplantation using organs from DWCH must be clarified. We assessed transplant outcomes of recipients of organs from DWCH. MATERIAL AND METHODS Retrospective analysis of the Scientific Registry of Transplant Recipients data from January 1, 2000 to December 31, 2014 identified 8385 cases of transplants from DWCH. A Cox-proportional hazard regression model and log-rank test were used to compare patient survival and hazard levels of various cancer types. RESULTS DWCH was an independent risk factor of 5-year patient survival (HR=1.089, 95% CI: 1.009-1.176, P=0.03) and graft survival (HR=1.129, 95% CI: 1.056-1.208, P<0.01) in liver and heart transplantation (patient survival: HR=1.112, 95% CI: 1.057-1.170, P<0.01; graft survival: HR=1.244, 95% CI: 1.052-1.472, P=0.01). There was no remarkable difference between the 2 groups in kidney and lung transplantation. Donors with genitourinary and gastrointestinal cancers were associated with inferior outcomes in kidney transplantation. Transplantation from donors with central nervous system cancer resulted in poorer survival in liver transplant recipients. Recipients of organs from donors with hematologic malignancy and otorhinolaryngologic cancer had poorer survival following heart transplantation. CONCLUSIONS Under the current donor selection criteria, recipients of organs from DWCH had inferior outcomes in liver and heart transplantation, whereas organs from DWCH were safely applied in kidney and lung transplantation. Specific cancer types should be cautiously evaluated before performing certain types of organ transplantation.